Category Archives: Drugs for Diabetes

Particular Diabetes Drugs May Protect Your Heart and Kidneys

 

Blood pressure control is also extremely important for protection of heart and kidneys

I’ve been reticent to tout the putative heart-protective effects of diabetes drugs in the classes called SGLT2 inhibitors and GLP-1 receptor agonists. Frankly, their supposed kidney-protective effects haven’t even been on my radar. My hesitation to report on these matters stems from:

Maybe if Big Pharma sent me a nice check….

The GLP-1 receptor agonists seem to have beneficial effects on both heart and kidney. With SGLT2 inhibitors, renal benefits may be more prominent than cardiac. Also note that any beneficial heart or renal effects may be attributable only to certain drug within the class, and not a class effect.

For what it’s worth, the American Diabetes Association recently hosted a conference on these issues. I assume the ADA endorses the report written by three experts, two of whom have received some sort of compensation from pharmaceutical companies. This doesn’t necessarily mean they are biased. Some excerpts:

Since patients with diabetes are at increased risk for CV [cardiovascular] and renal events, reducing the risk of these events is of primary interest to improve outcomes in the long-term. [Cardiovascular events usually refers to heart attacks, strokes, and death from those. Renal events would be high loss of protein through the kidneys, impaired kidney function or chronic kidney disease, or the need for dialysis.]

SGLT2 inhibitors and GLP-1 RAs have dramatically changed the treatment landscape of type 2 diabetes due to their established CV benefits, and the observed improvements in renal function seen with these classes of agents are currently undergoing intense investigation.

***

It is now apparent that both SGLT2 inhibitors and GLP-1 RAs show consistent reductions in major adverse cardiovascular events for patients with established cardiovascular (CV) disease, and both appear to have renal benefits as well.

***

The nephron is the microscopic structural and functional unit of the kidney.

Renal effects of GLP-1 receptor agonists

These drugs may exert their beneficial actions on the kidneys through their effects on lowering blood glucose and blood pressure and by reducing the levels of insulin.

For GLP-1RAs, these [studies] include ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, HARMONY with albiglutide, and REWIND with dulaglutide.

All these studies indicate that albuminuria [protein loss through urine] is reduced during treatment with GLP-1 RAs, and eGFR [estimated glomerular filtration rate, a measure of kidney function] appears to be stabilized.

These benefits are seen independently of HbA1c, weight, and blood pressure variations.

***

Heart attack is only one type of cardiovascular event

Cardiovascular effects of GLP-1 receptor agonists

Large CV outcomes trials with GLP-1 RAs have shown that these agents can reduce the risk of major adverse CV events, CV mortality, and all-cause mortality.

These CV benefits appear to be related to four distinct mechanisms:

    • Improve myocardial [heart muscle] performance in ischemic heart failure [caused by poor blood flow to heart]
    • Improve myocardial survival in ischemic heart disease
    • Ameliorate endothelial dysfunction [endothelium is the lining of arteries]
    • Decrease markers of CV risk.

***

Renal effects of SGLT2 inhibitors

  • However, many potential mechanisms have been linked to the renoprotective effects of SGLT2 inhibitors.
  • These include reduction of blood pressure, improved metabolic parameters, reduced volume overload, reduction in albuminuria, and glomerular pressure.
  • For the latter, SGLT2 inhibition appears to reduce hyperfiltration via a tubuloglomerular feedback mechanism.
  • Clinical data from CV outcomes trials have shown consistent variations in eGFR and reduction in death from renal causes with empagliflozin, canagliflozin, and dapagliflozin.
  • However, to gain more information about the renal effects of these agents, dedicated renal outcomes trials are needed to study reductions in albuminuria, changes in eGFR, number of patients reaching end-stage renal disease, need for dialysis, and deaths due to kidney failure.

***

Key Messages from the authors

Large CV outcomes trials have shown that both SGLT2 inhibitors and GLP-1 RAs are associated with significant reductions in CV events in patients with elevated CV risk.

From CV outcomes trials both classes of agents also appear to have renal benefits, although large dedicated studies are needed to establish the magnitude of this potential benefit

The mechanism of action at the basis of CV and renal benefits of SGLT2 inhibitors and GLP-1 RAs is complex, multifactorial, and still not completely understood.

I’m still skeptical but will keep an open mind.

Steve Parker, M.D.

PS: Bold emphasis above is mine.

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Review Article Supports Tight Control in Diabetes

What are reasonable blood sugar and HgbA1c goals for folks with diabetes? The experts continue to debate. If I had diabetes, I’d want my glucose levels as close to normal as possible. On the other hand, if I had terminal cancer, I’d be fine with higher levels.

In Diabetes Care:

Glycated hemoglobin targets have been given in guidelines for the last three decades, mostly without change at around 6.5–7.0% (47–53 mmol/mol). Personalization of such targets has also long been advocated, but often with little and inappropriate guidance. More recently some have suggested higher targets might be indicated, and more specifically lower targets avoided, even in those in whom they are easily attained without seeming burden or risk. Prospective data from randomized and observational studies, in people with type 2 diabetes and indeed those without diabetes, find cardiovascular and mortality risk are uniformly lowest at lower levels including into the normal range. In some studies with large populations, a high proportion of people are found to attain such levels, and the UK Prospective Diabetes Study (UKPDS) and more recent studies appear to confirm the importance of starting low and continuing long. Studies of cardiovascular events and mortality in people with diabetes will already factor in any effect of hypoglycemia, which therefore should not be double-counted in setting targets. Nevertheless, some factors should lead to modification of target levels, and these will include experience of hypoglycemia where therapy change and glucose monitoring cannot ameliorate it and sometimes prospectively in those at social or occupational risk. The fact that clinical experience will modify targets emphasizes that targets will not be stable over time but will change, for example, with occurrence of adverse events or perceptions of increase/decreased burden of therapy. The evidence suggests that glucose control takes 5 years or more to have any impact on vascular outcomes or mortality, so targets may also be higher in those with shorter life expectancy or higher health burden or simply reflect individual preferences. This article discusses the evidence behind these conclusions.

Source: Controversies for Glucose Control Targets in Type 2 Diabetes: Exposing the Common Ground | Diabetes Care

Steve Parker, M.D.

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U.S Is #1 in Diabetes Drug Prices

I don’t have the resources to confirm the figures below, but I won’t be surprised if accurate. From Public Interest on Twitter:

https://platform.twitter.com/widgets.js

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Not Very: How effectively does cinnamon treat diabetes?

Be aware there are several kinds of cinnamon

Pharmacist Scott Gavura writes at Science Based Medicine:

Given the consequences of diabetes, self-management is something I want to encourage, not discourage. Without a commitment from the patient to take an active role in managing their diabetes, any treatment plan is doomed to fail. So is self-treatment with dietary supplements a wise idea? There’s an array available, and patients regularly ask about the latest treatment “Big Pharma doesn’t want you to know about”. That treatment used to be chromium. Ginseng was popular for a time, too. Fenugreek and bitter melon are used as well. One of the most persistently popular treatments is cinnamon. Like any other herbal remedy, most sources will tell you that it’s been used for “thousands of years” as a medicinal herb. As a treatment for diabetes, I have my doubts. While reports of diabetes go back to 1552 BCE, the ability to measure the effectiveness of any diabetes treatment only goes back a few decades. Interest in cinnamon as a treatment seems to have started with in vitro tests but gained some plausibility in 2003, when a study from Alam Khan suggested several grams of cassia cinnamon per day could lower fasting blood glucose. Khan randomized Type 2 diabetes to 1g, 3g, or 6g of cinnamon for 40 days. All three groups improved their fasting blood glucose, and blood lipid levels, but there was no effect on A1C.Like trials with any other supplement or herbal product, the primary question we must answer is “What exactly was studied?” The cinnamon you have in your kitchen may be a single species of plant or a mix of different cultivars. Ceylon cinnamon (Cinnamommum verum) is more commonly found in the West. Cassia cinnamon (Cinnamomum aromaticum) is the version of cinnamon that’s been studied in trials. The chemical hydroxychalcone has been identified as a potential active ingredient, which is believed to modify the sensitivity of cells to insulin, enhancing their uptake. If that’s the true mechanism of action, then it would work in a manner similar to that of the drugs Avandia, Actos, and metformin (Glucophage). Given the active ingredient (or ingredients) have not yet been definitively isolated, the issue of studying cinnamon is problematic. There’s no way to assess the potency of any batch, which complicates any evaluation. And that may be a reason why the research with cinnamon is inconsistent, and on balance, not impressive.

While the Khan study looked promising, supplementary studies have failed to consistently show beneficial effects.

Source: How effectively does cinnamon treat diabetes? – Science-Based Medicine

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Insulin Is Much Cheaper in Mexico

Great article by Robin Cressman. RTWT.

“Just a week before the trip [to Tijuana, Mexico], I was down to my very last vial of Humalog. It was June and I was close, but still so far, from hitting my $5,000 deductible for the year, which meant I was still paying full price out of pocket for all of my medical costs until I hit that figure. I had started the year low on supplies (a rookie mistake that I now know to avoid) and had been juggling bills from Dexcom, my doctor’s office, and my pump supplier for months, trying to only use our health savings account but often having to pull out credit cards to cover the costs. I called my pharmacy and asked to fill a single vial of Humalog, and the cost was $248.13. I hung up the phone. Instead I went to Walmart and for the first time bought vials of Novolin NPH and Regular for $24.99 each. It was those vials that were serving as my backup insulin a week later when I found myself in that pharmacy in Tijuana.”

Source: Crossing Borders to Afford Insulin – T1International

Whether it’s legal or not, I don’t know. I do think Big Pharma has made it illegal for me to go down to Mexico, buy a bunch of insulin, and sell it to my patients.

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Beware Fournier Gangrene If You Take an SGLT2 Inhibitor for Diabetes

The FDA is warning doctors about the possibility of Fournier Gangrene in folks taking a particular class of diabetes drug. This gangrene is a nasty infection that I’ve seen only a few times, always in men. The FDA reports cases in both men and women taking SGLT2 inhibitors.

“Patients should seek medical attention immediately if you experience any symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell. These symptoms can worsen quickly, so it is important to seek treatment right away.”

Source: FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes | FDA

Exercise and proper diet can reduce your need to take drugs for diabetes.

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Is There a Role for Magnesium Supplementation in Type 2 Diabetes?

Not the magnesium used in the study at hand

I hadn’t thought so until I read about an experiment published in 2003. Now I’m wondering.

The study was done in northern Mexico and all participants were taking glibenclamide, a sulfonylurea known as glyburide in the U.S. Importantly, study participants had low blood magnesium levels at the outset.

So if you’re not a hypomagnesemic Mexican taking glibenclamide, results may not apply to you.

Nevertheless, results were impressive. Compared to the control group, magnesium supplementation…

  • reduced insulin resistance
  • fasting glucose was 144 mg/dl (185 in controls)
  • Hemoglobin A1c was 8% (10% in controls)

The experiment lasted 16 weeks and the specific form of magnesium used was magnesium chloride solution.

Maybe we should be checking magnesium levels more often. BTW, magnesium supplements are difficult for our bodies to absorb. I know of at least three magnesium compounds: oxide, citrate, and chloride. There are probably others. Degree of absorption varies from one to the other. Adding a supplement on top of kidney impairment could cause toxicity.

The researchers conclude:

Oral supplementation with MgCl2 solution restores serum magnesium levels, improving insulin sensitivity and metabolic control in type 2 diabetic patients with decreased serum magnesium levels.

Source: Oral Magnesium Supplementation Improves Insulin Sensitivity and Metabolic Control in Type 2 Diabetic Subjects | Diabetes Care

 

Physician Organizations Fight Over How Aggressively to Treat Diabetes

If you’re a patient, you probably don’t like to hear this. You like to think that doctors have looked carefully at the appropriate scientific studies, understand  the underlying pathophysiology in detail, then reach a consensus on treatment. Sorry, but not in the case of diabetes. NPR has the story. For example:

A major medical association today suggested that doctors who treat people with Type 2 diabetes can set less aggressive blood sugar targets. But medical groups that specialize in diabetes sharply disagree.

Half a dozen medical groups have looked carefully at the best treatment guidelines for the 29 million Americans who have Type 2 diabetes and have come up with somewhat differing guidelines.

The American College of Physicians has reviewed those guidelines to provide its own recommendations, published in the Annals of Internal Medicine. It has decided that less stringent goals are appropriate for the key blood sugar test, called the A1C.

“There are harms associated with overzealous treatment or inappropriate treatment focused on A1C targets,” says Dr. Jack Ende, president of the ACP. “And for that reason, this is not the kind of situation where the college could just sit back and ignore things.”

The ACP, which represents internists, recommends that doctors aim for an A1C in the range of 7 to 8 percent, not the lower levels that other groups recommend.

Source: The American College of Physicians Recommends A1C Levels Between 7 And 8 Percent : Shots – Health News : NPR

I come down in favor of the lower HgbA1c values.

From 2012: Largest Healthcare Fraud Settlement In History Involves T2 Diabetes Drug Avandia

Your friendly neighborhood drug supplier

Your friendly neighborhood drug supplier

This will help you understand why I favor diet modification over drug therapy for type 2 diabetes:

“Global health care giant GlaxoSmithKline LLC (GSK) agreed to plead guilty and to pay $3 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of certain prescription drugs, its failure to report certain safety data, and its civil liability for alleged false price reporting practices, the Justice Department announced today. The resolution is the largest health care fraud settlement in U.S. history and the largest payment ever by a drug company. GSK agreed to plead guilty to a three-count criminal information, including two counts of introducing misbranded drugs, Paxil and Wellbutrin, into interstate commerce and one count of failing to report safety data about the drug Avandia to the Food and Drug Administration (FDA). Under the terms of the plea agreement, GSK will pay a total of $1 billion, including a criminal fine of $956,814,400 and forfeiture in the amount of $43,185,600. The criminal plea agreement also includes certain non-monetary compliance commitments and certifications by GSK’s U.S. president and board of directors. GSK’s guilty plea and sentence is not final until accepted by the U.S. District Court. GSK will also pay $2 billion to resolve its civil liabilities with the federal government under the False Claims Act, as well as the states. The civil settlement resolves claims relating to Paxil, Wellbutrin and Avandia, as well as additional drugs, and also resolves pricing fraud allegations.”

Source: GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data | OPA | Department of Justice

Regarding Avandia:

“The United States alleges that, between 2001 and 2007, GSK failed to include certain safety data about Avandia, a diabetes drug, in reports to the FDA that are meant to allow the FDA to determine if a drug continues to be safe for its approved indications and to spot drug safety trends. The missing information included data regarding certain post-marketing studies, as well as data regarding two studies undertaken in response to European regulators’ concerns about the cardiovascular safety of Avandia. Since 2007, the FDA has added two black box warnings to the Avandia label to alert physicians about the potential increased risk of (1) congestive heart failure, and (2) myocardial infarction (heart attack). GSK has agreed to plead guilty to failing to report data to the FDA and has agreed to pay a criminal fine in the amount of $242,612,800 for its unlawful conduct concerning Avandia.”

And…

“In its civil settlement agreement, the United States alleges that GSK promoted Avandia to physicians and other health care providers with false and misleading representations about Avandia’s safety profile, causing false claims to be submitted to federal health care programs. Specifically, the United States alleges that GSK stated that Avandia had a positive cholesterol profile despite having no well-controlled studies to support that message. The United States also alleges that the company sponsored programs suggesting cardiovascular benefits from Avandia therapy despite warnings on the FDA-approved label regarding cardiovascular risks. GSK has agreed to pay $657 million relating to false claims arising from misrepresentations about Avandia. The federal share of this settlement is $508 million and the state share is $149 million.”

 

Are Some T2 Diabetes Drugs Better Than Others?

From MPT:

“The number of type 2 diabetes drugs that have a proven cardiovascular benefit jumped from one to three this year, highlighting the changing landscape for diabetes treatments.”

Source: Year in Review: Type 2 Diabetes | Medpage Today

The article notes that liraglutide (Victoza), a GLP-1 analogue, was associated with a 13% relative risk reduction in a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Semaglutide, an experimental GLP-1 analogue, also has evidence for cardiovascular death prevention.

Another diabetes drug, Jardiance or empagliflozin, also has evidence for cardiovascular death prevention. Jardiance is an SGLT2 inhibitor.

Read the full MPT article for more details. I find the cost of these drugs to be an interesting yet little discussed detail.

Let’s assume these drugs actually reduce cardiovascular disease risk in T2 diabetics. What if they increase death and disease rates from cancer and infection? You don’t hear much about that, do you?

We still don’t know much about the long-term adverse effects of most of our diabetes drugs. That’s one reason I tend to favor diet modification as a primary diabetes treatment.

No degludec up in here!